Research involves the development of novel immunotherapeutic approaches to cancer, including the design and analyses of recombinant vaccines directed against gene products of oncogenes and antigens overexpressed in tumors. Vaccine targets include human carcinoembryonic antigen (CEA), point mutated ras oncogenes, prostate specific antigen (PSA), the muc-1 breast, lung, and pancreatic associated mucin, and the c-erbB/2 oncogene. Vehicles for vaccine delivery for induction of host cellular immune responses include recombinant vaccinia (rV), replication defective avian pox viruses, DNA plasmids, peptides, and recombinant proteins. A Phase I clinical trial recently completed demonstrated that advanced carcinoma patients vaccinated with a recombinant vaccinia virus containing the CEA gene (rV-CEA) could elicit cytotoxic T-cell (CTL) responses to the self antigen CEA. The actual epitopes recognized by these T-cells were defined and used to establish CTL lines and clones. The utility of these and other CTL lines in the adoptive transfer of epitope specific T-cells lines is currently under investigation.Vaccine trials employing CEA CTL peptides, recombinant CEA, and replication defective avian pox virus recombinants containing CEA, alone and in combination with rV-CEA, are being designed. Studies are ongoing in the elucidation and analyses of agonist and antagonist peptides of the identified CEA CTL immunodominant epitopes. Initial studies have indicated that peptides can be designed that are more efficient than the natural peptide in the generation of cytotoxic T-cell lines. Studies are also ongoing with a recombinant vaccinia PSA vaccine, and PSA CTL immunodominant epitope peptides recently identified. A Phase I clinical trial is now in progress in which peptides reflecting ras oncogene point mutations at codon 12 are administered to patients whose tumors have been shown to contain the individual mutation. These studies have shown the induction of both CD4+ helper T-cells and CD8+ CTL specific for the mutated ras peptide and not proto-ras or other mutations. Ongoing studies include the use of multidimensional fusion proteins as immunogens and the exploitation of T-cell co-stimulatory molecules in both gene therapy and vaccine strategies.